Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness

Key Points Question Do patients hospitalized for COVID-19 have long-term cognitive, psychiatric, or neurological complications compared with healthy controls and matched patients hospitalized for non–COVID-19 medical conditions of similar severity? Findings In this matched cohort study including 345 participants, patients hospitalized for COVID-19 performed worse than healthy controls on cognitive, psychiatric, and neurological tests. However, compared with hospitalized controls matched for age, sex, and severity of disease, the impairment of brain health was similar. Meaning This study suggests that the brain health of patients was impaired after severe COVID-19, but no more than the brain health of patients hospitalized for other diseases of similar severity.


Introduction
Impaired brain health after SARS-CoV-2 infection remains common 3 years after the outbreak of COVID-19, 1 echoing impairments seen in previous virus pandemics. 2,3The long-term effects of COVID-19 are associated with more than 200 symptoms, affecting 65 million individuals worldwide. 4,57][8] However, long-term cognitive and neuropsychiatric sequelae also occur after non-COVID-19 conditions, such as pneumonia, 9 myocardial infarction, 10 and other diseases, including those requiring admission to the intensive care unit (ICU). 11[14] Hence, to discern the nature, extent, and trajectories of brain health complications specific to COVID-19, long-term prospective studies are required that involve clinical in-person evaluations of patients with COVID-19 and controls from cohorts appropriately matched for the degree of critical illness and level of hospitalization. 15re, we performed, to our knowledge, the first prospective, face-to-face, posthospital follow-up to assess whether long-term cognitive, psychiatric, or neurological complications among patients hospitalized for COVID-19 differ from those among healthy controls and carefully matched patients hospitalized for (1) pneumonia, (2) myocardial infarction, and (3) non-COVID-19, ICU-requiring conditions.

Study Design and Participants
Participants were evaluated between November 1, 2021, and February 28, 2023 (eFigure 1 in Supplement 1).eMethods 1 and 2 in Supplement 1 include detailed inclusion and exclusion criteria.
The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline and was reviewed and approved by the Danish Regional Committee on Health Research Ethics in Copenhagen.All participants gave written consent.

COVID-19 Case Cohort
We prospectively enrolled all patients hospitalized for COVID-19 at Rigshospitalet, a tertiary care hospital in Copenhagen, Denmark, from March 1, 2020, to March 31, 2021.Patients hospitalized for COVID-19 during the same time period at another Copenhagen hospital (Gentofte Hospital) were also enrolled.

Matched Control Cohorts
Controls were matched for age and sex; hospitalized controls were additionally matched for ICU admission.Control patients were hospitalized between March 1, 2020, and June 30, 2021, for non-COVID-19 pneumonia, myocardial infarction, or non-COVID-19, ICU-requiring illness (eTable 1 in Supplement 1) and were admitted to Rigshospitalet or Gentofte Hospital.Exclusion criteria were

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Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness previous hospitalization for COVID-19 and recent (<3 months) SARS-CoV-2 infections.Healthy controls were 18 years of age or older and without hospitalization in the preceding 2 years.

Clinical Follow-Up Assessments
Eligible patients were contacted by telephone and email and invited for in-person follow-up a mean (SD) of 19.4 (1.6) months after discharge (6-month follow-up data are available elsewhere 16 ).
Participants underwent a structured, face-to-face interview by 2 trained physicians supervised by senior neurology (D.K.) and senior psychiatry (M.E.B.) consultants.

Neurological Examination
We assessed sensorimotor and cerebellar functions and cranial nerves, including the 4-item Pocket Smell Test "scratch and sniff" for olfaction (range, 0-4; <4, abnormal).Neurological signs were quantified with the Neurological Evaluation Scale (26 items, rated on a scale from 0 to 2 [no impairment, mild impairment, and severe impariment] except snout and suck reflexes rated only 0 and 2 [no impairment and impairment]).

Self-Experienced Symptoms and Fatigue After Hospitalization
We collected subjective cognitive and neuropsychiatric symptoms using semistructured interviews (eMethods 3 in Supplement 1).Symptoms were registered if they were of new onset or had worsened after hospitalization and other causes were excluded.For controls with a previous SARS-COV-2 infection, typical symptoms of COVID-19, such as anosmia and dysgeusia, were documented only if associated with hospitalization.The Fatigue Assessment Scale was administered to investigate mental and physical fatigue.Total scores ranged from 10 to 50 (<22 indicating no fatigue; 10 items, scored from 0 to 5 [never to always]).

Basic Clinical Data
We collected data on age, sex, educational level, comorbidities, smoking status, alcohol consumption, delirium during admission, laboratory test findings, brain imaging, cerebrospinal fluid findings, electroencephalograms, nerve conduction studies, and electromyograms.An ordinal scale was used to record hospital disease severity. 20We made 3 attempts to contact eligible individuals by telephone and sent out written invitations before considering them lost to follow-up (Figure 1; eFigure 1 in Supplement 1).

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Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness

Primary, Secondary, and Exploratory Outcomes
The primary outcome was overall cognition assessed by the SCIP scores and log-transformed scores (32 -MoCA [all scores are subtracted from 32 and the new value is log-transformed]).Secondary outcomes were log-transformed Trail Making A and B scores, HAM-A and HAM-D scores, and Neurological Evaluation Scale scores.In addition, exploratory outcomes (eMethods 4 in Supplement 1) included changes over time in MoCA score and symptom frequency, neurological examination results, psychiatric diagnoses, number of subjective symptoms, and fatigue.a A total of 56 of 511 patients with COVID-19 (11.0%) were hospitalized at another hospital during the same time period and considered for follow-up; 3 patients in the intensve care unit (ICU) were included from the group of patients hospitalized with non-COVID-19 illness.

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Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness binary and ordinal outcomes, 95% CIs and P values were based on Wald statistics.Effect heterogeneity P values were based on likelihood ratio statistics.
Analyses of change for MoCA scores at hospital discharge, 6 months, and 18 months among patients with COVID-19 were performed in linear mixed-effects models with patients as random effects.Sex and age were used as matching variables for adjustment of the models because confounders that remain constant within patients will not alter the results.
Analysis of change for patients with COVID-19 in binary variables at 6-month and 18-month followup was performed in logistic regression models with patients as random effects using the 7-point adaptive Gauss-Hermite quadrature for the computations with no confounder adjustment.The 95% CIs for the estimated ORs were based on Wald statistics.P values were based on likelihood ratio statistics.
All P values were 2-sided, and results were deemed statistically significant at P < .05.For exploratory outcomes, P values were left unadjusted, and a Bonferroni-adjusted α level of P < .001(0.05/48) was applied to assess significance on a multiplicity-adjusted 5% α level.Missing data were not imputed, and complete-cases analyses were reported.Statistical analyses were conducted in R, version 4.1.2[24]

Primary Outcomes Cognition
The estimated mean SCIP score at 18-month follow-up was 59.0 (95% CI, 56.9-61.and number of days to follow-up (Figure 2; eTables 6 and 7 in Supplement 1).

Neurological Symptom Scales
The estimated mean score for the Neurological Evaluation Scale was higher (ie, worse performance) among patients with COVID-19 than among healthy controls (RMD, 1.37 [95% CI, 1.11-1.69];P = .004)but was not higher than among hospitalized individuals (RMD, 1.06 [95% CI, 0.85-1.33;P = .59)(Figure 2; Table 2 and Table 3).Results were similar between patients in the ICU and those not in the ICU, with no significant difference between the groups in any of the secondary outcomes (Figure 2; eTables 6 and 7 in Supplement 1).Models followed the same adjustments as for primary outcomes.b Model adjusted for sex, age, admission length, time from hospitalization to follow-up, intensive care unit admission, and severity.

Exploratory Outcomes
c For description of scores, see eMethods 4 in Supplement 1.
d Missing data on 7 patients with COVID-19 and 1 control patient.
e Missing data on 1 patient with COVID-19.
f Missing data on 1 patient with COVID-19.
g Missing data on 2 patients with COVID-19.

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Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness

Longitudinal Data
Fifty-six patients with COVID-19 were examined 6 months after hospitalization (June 2020 to July 2021) with the MoCA, MINI, objective neurological examination, and symptoms interview.
There was an increased frequency from 6 months to 18 months of psychiatric diagnoses assessed using the MINI (from

Sensitivity Analyses
We conducted sensitivity analyses on primary outcomes between subgroups of patients in the ICU and not in the ICU.The overall difference between cases and controls remained nonsignificant when adjusted for several additional factors, including sex, age, admission length, time from hospitalization to follow-up, disease severity, educational level, grade, depression, alcohol abuse, smoking, malignant neoplasms, previous medical and psychiatric history, and delirium (eTables 14-17 in Supplement 1).

Discussion
In this prospective cohort study, patients with COVID-19 performed worse than healthy controls in all cognitive, psychiatric, and neurological tests 18 months after hospitalization.Patients with COVID-19

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Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness more often had new psychiatric diagnoses, fatigue, and impaired olfaction than healthy controls.
However, patients with COVID-19 had similar outcomes as hospitalized controls, except for executive function and impaired olfaction.In the group with COVID-19, we observed a substantial improvement in cognitive scores between discharge and 18-month follow-up, but not between 6-month and 18-month follow-up.Patients with COVID-19 also experienced an increase in psychiatric comorbidities, neurological findings, and subjective symptoms involving memory and sleep between 6-month and 18-month follow-up.
7][28] We found that 38% of patients with COVID-19 had MoCA scores below 26 at 18-month follow-up and performed worse in all cognitive tests compared with the healthy population, consistent with previous research. 8A large study also identified a higher risk of mild cognitive decline among older patients hospitalized with COVID-19 compared with healthy controls. 27Our findings showed overall similar cognitive performances between patients with COVID-19 cases and matched controls hospitalized for non-COVID-19 causes.This finding corroborates a 4-month follow-up study comparing a cohort of patients with COVID-19 with a cohort with sepsis, which found no disparity between the cohorts in MoCA scores. 14These findings underscore the fact that all these medical conditions are associated with cognitive impairment. 9,11,29rroborating previous studies, we found that anxiety and depression were more frequent among patients with COVID-19 compared with healthy controls but no more frequent than among other hospitalized patients. 7In line with 2 retrospective studies, 12,30 psychiatric diagnoses assessed by the MINI were also comparably prevalent among patients with COVID-19 and hospitalized controls.
As for neurological outcomes, patients with COVID-19 more often had neurological soft signs 31,32 compared with healthy controls but not compared with hospitalized controls.Underlying factors such as cardiovascular disease, hypertriglyceridemia, and hypertension can cause subtle neurological abnormalities 33 and may explain the similarity between patients with COVID-19 and controls.During the neurological examination, only impaired olfaction was more common among patients with COVID-19 (38.7%) than healthy controls (16.0%).Neurological abnormalities, including olfactory dysfunction, have been previously reported among patients with COVID-19. 34Subjective anosmia was also more frequent among patients with COVID-19, which might be explained by invasion of SARS-CoV-2 in olfactory pathways. 35 to longitudinal results, the patients with COVID-19 showed decreasing MoCA scores and increasing subjective memory deficits between follow-up visits.The previous literature is heterogenous, reporting improvement, 7 unchanged symptoms, 34 or declines. 27,36In particular, cognitive decline was observed between 2 and 12 months after hospitalization in one study, 36 while another study found an association between long-term cognitive deterioration and COVID-19 among older individuals. 27Furthermore, cognitive scores might decrease over time, especially among older populations, 37 and we did notice increased psychiatric diagnoses (from 17.9% to 32.1%) and neurological abnormalities (from 25.0% to 51.8%) among patients with COVID-19 over time.One explanation could be selection bias, where individuals who chose to participate in both follow-up visits might have had ongoing concerns and desired further evaluation.However, previous studies have reported similar rates of psychiatric morbidity (45%) 26 and neurological abnormalities (64%) 34 1 year after infection.Altogether, while it is essential to interpret these findings with caution due to the limited longitudinal data available, the possibility of worsening brain health over time cannot be ruled out.

Limitations
This study has some limitations.First, the follow-up period was relatively long, which could have affected the observed frequency of some outcome measures.Second, the groups were slightly different at baseline, with the hospitalized group being older and healthy controls having relatively

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Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness fewer comorbidities and overall higher educational levels than patients with COVID-19.Nonetheless, our results remained unchanged when adjusted for age, comorbidities, and educational level.Third, the inclusion period covered different strains of SARS-CoV-2 with varying virulence and potential for long-term effects.Fourth, some controls (43.2% of hospitalized controls and 54.0% of healthy controls) had been previously infected with SARS-CoV-2.However, these individuals had not been hospitalized for COVID-19, and their infections had been mild or asymptomatic and occurred at least 3 months prior to study enrollment.Fifth, we included the SCIP test, which has no ceiling effect and covers all the most relevant cognitive domains, but the cognitive test battery was comparably small.
Sixth, for obvious reasons, cognitive scores from before the pandemic were unavailable, which precludes precise quantification of brain health deficits compared with premorbid conditions, even though we excluded people with known preexisting cognitive impairment.

Conclusions
This cohort study suggests that patients hospitalized with COVID-19 had worse cognitive, neurological, and psychiatric outcomes at 18-month follow-up than healthy controls.However, compared with carefully matched patients requiring hospitalization for pneumonia, myocardial infarction, or non-COVID-19, ICU-requiring illness, there were no statistically significant differences.
Because healthy controls had fewer comorbidities than hospitalized individuals, we conclude that multimorbidity plays a role in both hospitalization and lasting associations with brain health.
Although studies with broader cognitive test batteries are needed to confirm these findings, brain health after COVID-19 seems overall comparable to that after other diseases of similar severity.
was assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP; lower scores indicate greater cognitive impairment [minimun 0, no maximum, mild impairment <75]) and the Montreal Cognitive Assessment (MoCA; scores <26 are abnormal and indicate cognitive impairment; lower scores indicate greater cognitive impairment [range, 0-30]). 17,18Executive functions were tested with Trail Making Tests A and B (higher scores indicate greater executive dysfunction [maximum time, 5 minutes; Trail A deficient, >78 seconds; Trail B deficient, >273 seconds]). 19Neuropsychiatric Interview We evaluated depression and anxiety using the Hamilton Anxiety Rating Scale (HAM-A; higher scores indicate greater anxiety [range, 0-56]) and the Hamilton Depression Rating Scale (HAM-D; higher scores indicate greater depression [range, 0-52]).Patients were screened for newly acquired psychiatric disorders using the Mini International Neuropsychiatric Interview (MINI), version 5.0.Electronic health records were screened to confirm new onset of the disorder, according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.

Table 1 .
Baseline Characteristics of Patients With COVID-19, Hospitalized Controls, and Healthy Controls Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness Comparisons between patients with COVID-19 and healthy controls were adjusted for sex, age, BMI, educational level, alcohol abuse, and smoking.Comparisons with hospitalized controls were adjusted for age, sex, ICU admission, total number of admission days, number of days to follow-up, and disease severity.We found similar results with no significant difference in SCIP and MoCA scores when stratifying for ICU admission in models adjusted for age, sex, total number of admission days,

Table 1 .
Baseline Characteristics of Patients With COVID-19, Hospitalized Controls, and Healthy Controls (continued) Patients with COVID-19 were slower (had higher scores) in completing both Trail Making Tests A and B compared with healthy controls.Trail Making Test A scores were 19% higher (RMD, 1.19 [95% CI, 1.07-1.33];P = .002)and Trail Making Test B scores were 32% higher (RMD, 1.32 [95% CI, 1.16-1.51];P < .001)among patients with COVID-19 (eFigure 2 in Supplement 1; Table 2 and Table 3).However, when comparing patients with COVID-19 and hospitalized controls, only the Trail Making Test B 9I conversion factors:To convert leukocytes to cells ×109per liter, multiply by 0.001; CRP to milligrams per liter, multiply by 10.0; creatinine to micromoles per liter, multiply by 88.4; ALT to microkatals per liter, multiply by 0.0167; D-dimer to nanomoles per liter, multiply by 5.476; creatine kinase to microkatals per liter, multiply by 0.0167; and LDH to microkatals per liter, multiply by 0.0167.aLinearmodel was used for comparison of mean values, log-linear model for comparison of median values, and Pearson χ 2 for categorical variables.bShortcycle spans 1 to 2 years, medium cycle spans 3.5 to 4 years, and long cycle comprises 5 years, divisible into a 3-year bachelor's program and a 2-year master's program.cdMissing data from 18 hospitalized individuals.eMissingdata from 22 hospitalized individuals.fMissingdata from 1 hospitalized individual.gMissingdata from 55 hospitalized individuals and 1 patient with COVID-19.hMissingdata from 63 hospitalized individuals and 25 patients with COVID-19.iMissingdata from 63 hospitalized individuals and 79 patients with COVID-19.jMissingvalues from 43 hospitalized individuals and patients with 5 COVID-19.Figure 2. Primary Outcomes and 2 Secondary Outcomes Compared Between Patients With COVID-19 and Control Groups D Relative mean difference (RMD) of primary cognitive outcomes and secondary psychiatric and neurological outcomes.See eFigure 2 in Supplement 1 for other secondary outcomes.HAM-D indicates Hamilton Depression Rating Scale; MoCA, the Montreal Cognitive Assessment; NES, Neurological Evaluation Scale; and SCIP, Screen for Cognitive Impairment in Psychiatry.aRelative mean difference for MoCA scores refers to mean difference of 32 -MoCA score and for HAM-D and the NES to total score +1.b Models are adjusted for sex, age, body mass index, educational level, alcohol abuse, smoking, and intensive care unit (ICU) admission.cModels are adjusted for sex, age, admission length, time from hospitalization to follow-up, ICU admission, and disease severity.dModels are adjusted for sex, age, admission length, and time from hospitalization to follow-up.JAMA Network Open | Neurology

Table 2 .
Cognitive, Neurological, and Psychiatric Outcomes Compared Between Patients With COVID-19 and All Hospitalized Individuals

Table 3 .
Cognitive, Neurological, and Psychiatric Outcomes Compared Between Patients With COVID-19 and Healthy Controls Models are adjusted for sex, age, body mass index, educational level, alcohol abuse, smoking, and intensive care unit admission and include hospitalized individuals.Full results are presented in eTable 5 in Supplement 1.
b c For description of scores, see eMethods 4 in Supplement 1. d Missing data on 7 patients with COVID-19.e Missing data on 1 patient with COVID-19.f Missing data on 1 patient with COVID-19.g Missing data on 2 patients with COVID-19.

SUPPLEMENT 2. Data Sharing Statement
Inclusion and Exclusion Criteria (Methods) eMethods 2. Characteristics of Control Groups eMethods 3. Questionnaire on Subjective Symptoms (Methods) eMethods 4. Outcome Measures and Methods of Assessment (Methods) eTable 1. ICU Controls Admission Causes eTable 2. Baseline Characteristics of COVID-19, All Hospitalized Individuals, and Healthy Controls eTable 3. Baseline Characteristics of COVID-19 Non-ICU, Pneumonia, Myocardial Infarction and Healthy Controls eTable 4. Baseline Characteristics of COVID-19 ICU and ICU Controls eTable 5. Cognitive, Neurological, and Psychiatric Outcomes Compared Between COVID-19 Patients, All Hospitalized Individuals and Healthy Controls eTable 6. Cognitive, Neurological, and Psychiatric Outcomes Compared Between Non-ICU COVID-19 Patients and the Other Non-ICU Groups in Models Adjusted for Age and Sex (A) and Fully Adjusted (B) eTable 7. Cognitive, Neurological, and Psychiatric Outcomes Compared Between ICU COVID-19 and ICU Controls in Models Adjusted for Age Sex (A) and Fully Adjusted (B) eTable 8. Self-Reported Neuropsychiatric Symptoms in COVID-19 Patients and Hospitalized Controls at the 18 Months Investigation eTable 9. Neurological Examination Findings in COVID-19 Patients, Hospitalized Controls and Healthy Controls at the 18 Months Investigation eTable 10.New Onset Psychiatric Disorders Assessed With the MINI Interview in COVID-19 Patients, Hospitalized Controls and Healthy Controls at the 18 Months Investigation eTable 11.Fatigue Assessment Scale Scores Compared Between COVID-19 Patients, Hospitalized Controls and Healthy Controls eTable 12. Changes in Mean MoCA Score Over Time in COVID-19 Individuals eTable 13.Changes in Frequency of Neurological Findings, Psychiatric Diagnoses and Subjective Symptoms in COVID-19 Individuals Between 6-and 18-Months Follow-Up Visits eTable 14.Sensitivity Analyses for SCIP Scores in Non-ICU COVID-19 Patients and Non-ICU Hospitalized Controls eTable 15.Sensitivity Analyses for SCIP Scores in ICU COVID-19 and ICU Controls eTable 16.Sensitivity Analyses for MoCA Scores in Non-ICU COVID-19 Patients and Non-ICU Hospitalized Controls eTable 17.Sensitivity Analyses for MoCA Scores in ICU COVID-19 and ICU Controls eFigure 1. Detailed Flowchart of Inclusion Process eFigure 2. Secondary Outcomes Compared Between COVID-19 and Control Groups eFigure 3. MoCA Scores in COVID-19 Cases and Controls at 18-Month Follow-Up and Changes in Mean MoCA Scores Over Time in COVID-19 Cases eFigure 4. Radar Chart Showing Trajectories of Psychiatric Symptoms and Diagnoses (A) and Neurological Symptoms and Signs (B) From 6 to 18 Months After COVID-19 Hospitalization eReferences.